Garland R. Marshall

Garland R. Marshall pioneered computational approaches to peptide conformation and drug design, establishing molecular modeling as an essential tool for understanding structure-activity relationships. His development of computer-aided design software and the active analog approach transformed how medicinal chemists conceptualize receptor-ligand interactions.

Marshall was recruited to Washington University School of Medicine in 1966, where he constructed the second automated peptide synthesizer. Beginning in 1967, he applied emerging computer technology to molecular graphics and conformational analysis, developing methods that would mature into the SYBYL software package for computer-aided drug design. In 1979, he founded Tripos, Inc. to commercialize this technology, creating tools that became industry standards for three-dimensional molecular modeling.

His active analog approach introduced systematic conformational analysis to identify the bioactive conformation of flexible peptides. By comparing low-energy conformations of active and inactive analogs, Marshall's method identified spatial arrangements of pharmacophoric groups essential for receptor binding. This framework influenced the design of peptidomimetics across therapeutic areas, from angiotensin analogs to HIV protease inhibitors.

Marshall's research addressed HIV protease inhibitors for AIDS treatment beginning in 1987, and he later founded Metaphore Pharmaceuticals to develop metal-based enzyme mimetics, including a superoxide dismutase mimetic that advanced through clinical trials. His work on constraining peptide flexibility to enhance binding affinity established principles for rational peptidomimetic design that remain central to medicinal chemistry.

Marshall was selected for the inaugural ACS Medicinal Chemistry Hall of Fame and received the Merrifield Award. In the Department of Biochemistry and Molecular Biophysics, he continued teaching graduate courses in molecular modeling while investigating novel antibiotics targeting bacterial two-component regulatory systems and inhibitors of ErbB-family receptor dimerization for oncology applications.